The grant proposal presented here describes the development and experimental and clinical validation of a noninvasive method to reliably screen for and detect cardiac allograft rejection. A previously examined electrophysiologic parameter, the first fast negative deflection in the unipolar electrogram, termed UPPA, has been monitored following heterotopic canine transplantation, with a sensitivity and specificity for detecting rejection that is equivalent to standard endomyocardial biopsy techniques. However, these UPPA data can be obtained noninvasively using pacemaker telemetric technology by transcutaneously interrogating implanted pacemakers connected to epicardial pacemaker leads implanted on the allograft. In a series of laboratory experiments, this project will determine the principal factors that lead to changes in UPPA under both normal and abnormal conditions; will establish quantitative thresholds for the early detection of rejection with UPPA as compared with histologic evidence of rejection; will correlate these changes in UPPA during rejection with alterations in regional myocardial blood flow; will examine the effect of other electrophysiologic, mechanical and environmental factors on UPPA in normal hearts, in denervated hearts and in allografts undergoing early rejection; and will determine the optimal parameters for non-invasive telemetric monitoring, storage, analysis, and retrieval of UPPA data. Finally, the project will demonstrate the validity and cost- effectiveness of the UPPA monitoring system, both in-hospital and at home, in human cardiac allograft recipients. Such a system would decrease the cost and morbidity of screening endomyocardial biopsies, and may allow for closer surveillance and earlier diagnosis of rejection, with subsequent prolongation of allograft survival.